The quality of the pharmaceutical product is defined as one that is pure, correctly identified, effective and safe to use. Customers and patients have an ethical right to expect quality pharmaceutical product.
The warehouse plays a pivotal role in manufacturing quality products, as it is responsible for all incoming goods and for releasing finished products. Therefore there is GMP rules in place to ensure that material are handled and stored properly, while appropriate documentation is maintained.
GWP vs GDP
GWP refers to the practices specifically within the company warehouse. GDP refers specifically
to the transport and distribution of the product. Good Distribution Practice (GDP) and Good
Warehousing Practice (GWP) are each special parts of GMP.
GDP and GWP each have their own legal definitions and regulations. These regulations
recognize that product quality can be significantly impacted after manufacturing and packing have taken place. Once finished product is received into the warehouse, it does not undergo any further inspections or quality control tests. If the product is degraded or damaged at this point, there is nothing that
stops it from being given to the patient. There have been many cases of product being affected by poor warehouse storageconditions or rough handling in transport. Biopharmaceutical products often have temperature sensitive active ingredients that break down or degrade if exposed to heat or light, thus becoming ineffective. A pharmaceutical warehouse must be expertly managed and run in compliance in order for the company to protect and distribute quality product. GMP rules for the warehouse enable manufacturers to:
1. Protect medicine from damage during storage and transport
2. Prevent degradation of the product by exposure to adverse temperature conditions
3. Avoid mix-ups and contamination by other materials
4. Maintain product identity and traceability
5. Prevent time expired or damaged material or product from being used
What Comes into the Warehouse?
1. Non-production consumables (non GMP material), e.g., stationery, toilet paper, etc
2. Production materials consumed in processing e.g. filters, lubricants
3. Laboratory reagents e.g. buffers, chemicals
The last two items above will usually have their own QC approval processes.
The following goods will always appear on any production or packaging of materials. They are each governed by GMP quality control and release procedures. All these goods will be issued with unique lot numbers.
4. Manufacturing starting materials and chemicals
5. Packaging components e.g. blister pack film, bottles, caps, vials, seals
6. Printed matter e.g. labels, cartons, inserts/leaflets, pre-printed tubes
Typical Layout of the Warehouse
1. Warehouses are typically classified by the type of material they contain, e.g. raw
materials, packaging materials, intermediate or bulk product and finished product.
2. A typical warehouse will contain some or all of the areas described below-
3. Quarantine area for storing goods that have not yet been inspected or tested. Materials
stored in Quarantine cannot be used or released until approved by QC.
4. Some warehouse has Dangerous Goods Area to ensure the safety of the staff and the
facility. For e.g. flammable goods such as ethanol would be stored in this area.
Special storage conditions, such as flame-proof cabinets, are used here.
5. Some warehouse has a locked area for restricted goods, such as poisons and drugs of addiction. This area is restricted to specifically authorized staff.
6. A separate area for isolating faulty or recalled goods, ensuring that they are not issued
or sold by mistake.
7. A “reject” area reserved for rejected batches.
8. A cool room is usually operated at 2ºC- 8ºC, so temperature sensitive material (e.g.
vitamins) do not deteriorate. (It is important to regularly check that the cool room
temperature is within normal operating ranges. The cool room usually has quarantine
and a released area.)
9. The sampling booth is the first place where starting chemicals are opened. To protect
the material, the sampling room should have specific air controls to exclude outside
air from entering, and to control any dust generated from sampling to protect the
environment. (Pay particular attention to the air control systems, gowning and safe
handling of chemicals in this area.)
10. A “released” area for batches that have been successfully tested and passed for use.
Procedure for Receiving Materials into Warehouse
In the case of starting materials first arrive at the facility, they will always need to be checked to
see that
- Arrived from the approved supplier
- Are not damaged
- Are correctly labeled and identified with the supplier’s lot number for traceability purposes
- Are given a unique in house lot number
- Registered in inventory and
- Quarantined, then sampled for release testing
Some of these chemicals may also deteriorate when exposed to heat, so they may have to be
stored under controlled temperature, or even frozen.
Status labels
In addition to the identification information, each lot requires a status label, so that the status of
any material is evident. Status labels may be either:
- Physical labels on the container
- Electronics fields on a database
- Combination of physical and electronic
Note: Different companies may have different colors for the types of status labels used
1. Quarantine label - This label is used when the goods have not yet been tested and released
for use by the laboratory. Materials labeled Quarantine should not be used.
2. Hold label - The hold label indicates the material may have a problem and is under
investigation. Do not use under any circumstances.
3. Release label - The release label indicates the material is suitable for use or released for
supply. The batch has been tested and cleared by the quality department.
4. Approve label - The approved label indicates the material is suitable for use or released for
supply. The batch has been tested and cleared by the laboratory.
5. Reject label - The rejected label indicates that the batch has been assessed as unacceptable or
defective. Never use these materials. They should be located in separate, locked area.
Use of computer systems
Often, computer systems are used to control the inspection and test status of materials and products. If computers are used, materials and products may not need physical status labels, or even be stored in separate areas. Inventory status control computer systems used in warehouses must be validated for reliability and freedom from errors. There should be strict procedure in place and security levels instituted to ensure that information is accurately entered.
Warehouse Personnel and Training
Warehouse personnel need to be skilled in a number of different functions, including applying
the GMP rules specific to the warehouse, just like manufacturing personnel are trained in
applying GMP rules related to their areas. Some examples of the specific skills required to warehouse personnel:
1. Pack and label stock so that it is protected during transport.
2. Interpret environment monitoring displays such as temperature and humidity gauges.
3. Be able to ensure that materials and stocks are located under their correct storage
locations.
4. Use safe handling procedures according to each chemical’s material Safety Data Sheet
(MSDS).
5. Conduct stock takes and maintain inventory records.
6. Accurately locate and select the right stock from pick list and orders on a first-in, first out
basis. (FIFO/LILO-last in last out)
7. Recognize situations where products or chemicals may be at risk, e.g., spillage, broken pack, missing labels.
8. Safely operate picking machinery, such as a forklift or bay picker.
9. Accurately enter stock into the computer system inventory and maintain accurate paper records.
Preventing Contamination and Deterioration
To prevent contamination and deterioration of materials during warehousing, there are some
important warehouse rules that must be followed.
1. No pack should be left unsealed. This prevents possible dirt contamination from the
environment or pest infestation.
2. All chemical and products must be stored within their labeled temperature zones, for
example, products labeled- store at 2ºC- 8ºC, do not freeze, store below 25ºC.
3. Use FIFO system. Chemicals and medicinal products deteriorate over time, and generally
have expiry dates. Not rotating stock could result in partly degraded or aged materials being issued.
4. Follow the chemical spillage procedures to ensure that personnel and other products are
protected. Report all incidents to supervisor.
5. Keep outer doors and exits closed whenever not in use. Outside dust and pest may
contaminate the stock.
6. Never use material or product that is either unlabeled or not correctly labeled. If a label is
missing, it generally means the stock should not be used.
Contamination:- contamination refers to the presence of any foreign substances in a product. It may be:1. Physical e.g. foreign objects, dirt, dust, pollens 2. Chemical e.g. cleaning agents, lubricants, impurities, degradation products. 3. Microbiological e.g. bacteria, moulds, spores,
yeasts
Housekeeping in the Warehouse
A key to successfully operated warehouse is good housekeeping. The warehouse is a generally
very busy place, with constant movement of inventory in and out, as well as to different
warehouse locations internally. Good housekeeping, which generally means “Everything in its place”, minimizing the opportunities to mix-ups of goods, reduces the possibility of dispatch or
issue of incorrect goods, and improves warehouse safety.
1. Pest control: some of the pests that are attracted to pharmaceutical warehouses include rats, mice, birds, ants and cockroaches. Therefore GMP rules required that a manufacturing facility
- A nominated pest control officer
- Specific instructions or agreements with pest control companies
- Maps showing locations
- Documentation of all pest control treatments
- Having frequent waste collections
a) Outside air: the outside air is of course not controlled in any way. If the factory is left open,
wind will blow contamination into the factory, so it is important that the outer door is kept shut
when not in use. The outer door provides the first point of protection for the warehouse and the production area.
b) Receipt Area: this is where goods are unloaded off the delivery truck and assessed before brought into the warehouse. Notice that this area has an outer roller door and an inner curtain in order to prevent outside dirt or dust from entering the warehouse. An important GMP rule is to not have both the outer roller door and the inner barrier open at the same time. This area is some time refers as a “Black Zone”. This area is also the first point where outer bags and cartons are cleaned down, so that minimal dirt is transferred to the warehouse itself. If goods are unclean or
damaged, they should not be sent into the warehouse.
c) Warehouse Area: The warehouse itself is not a pressure controlled, but is cleaner than the receipt area. In the warehouse, goods should be stored off the floors and away from the walls, because moisture may be taken up through concrete walls and floors. This area is sometimes referred to as a “Grey Zone” since it is cleaner than outside, but still not clean enough to expose products to the environment.
d) Production Area: Some companies refer to the production area as a ”White or Clean Zone”, where only cleaned material may be taken. Generally goods transported to this area are on plastic pallets, since wooden pallets cannot be cleaned and can harbor fungus, mould and bacterial contamination. The production zone is pressure controlled to provide an air barrier to dirt and particles entry. In order to maintain positive pressure, it is critical to keep the doors between production and warehouse area closed. Before materials are taken into the production area, the
outer cartons that had arrived on the truck are generally removed, where possible, as an added precaution. Most companies also have different dress codes when moving from a Grey zone to a White zone.
3. Importance of controlling storage temperature
Temperature storage controls are important in the warehouse in order to ensure product integrity thought-out the product’s shelf life. Medicinal products damaged by exposure to extremes of temperature may escape detection, resulting in physical damage and/or loss of therapeutic effect.
Worst of all, it may not obvious at all.
For temperature controlled warehouse, companies are expected to create a temperature map of the facility. The map is used to identify the best places in the warehouse to store goods. An initial
study when creating this mp will reveal where problems would most likely be encountered e.g.,
storing goods against north-facing walls, close to room heaters, close to windows or near the
roof.
After initial mapping, temperatures are routinely monitored on a continuous or daily basis. This monitoring may reveal seasonal patterns where temperatures may rise or fall outside approved
limits. It is important, then, to continue to review temperature profiles in the warehouse over
time, particularly during summer and winter. Some companies monitor using an electronic
building management system.
Ambient temperature storage
The terms “room” or “ambient” temperature storage conditions have different meanings to
different companies and different regulators. It is now more common to use the term “temperate”
storage. Temperate storage has recently been defined as a storage temperature of between 15ºC
and 30ºC, with occasional excursions above the range. Temperate storage controls vary from
product to product, however, many licensed products stipulate an upper limit of 25ºC with no
lower limit apart from “protect from freezing”.
Additional requirements for temperature control
1. The condition of storage for the goods should be compatible with the storage conditions
specified on their labels.
2. Controlled storage environments should be monitored, using suitable temperature recording
devices. All records should be reviewed and filed, with their results tabulated and analyzed.
3. Refrigerated and freezing storage environments should be lifted with both an alarm and a
visual signal. This signal should permit resetting only by an authorized person.
4. If any temperature is found deviated outside the relevant recommended conditions for an
extended time, the manufacturer of the goods should be contacted and the suitability of the
product for use resolved.
5. Equipment used for monitoring temperature should be calibrated on a regular basis to ensure their accuracy.
How to create temperature map?
A simple temperature control example involves the physical location of material storage in the warehouse. The higher up the material stored in the warehouse, the hotter the temperature the goods will be exposed to, so an physical space near the ceiling without temperature controls will be inappropriate to store goods that need to be kept cool.
1. Study the temperature profile of the premises, and identify potential “hot” and “cold” areas
2. Study the areas of greatest potential risk using calibrated temperature and humidity monitoring
instruments.
3. Develop a temperature mapping validation protocol.
4. Based on the initial findings, commence monitoring on a regular basis.
5. Produce a temperature map of the premises.
6. Review the hot and cold areas when outside temperatures are extreme, for example, in the
summer and winter.
7. Review the controls of heating and cooling system.
8. Ensure an action plan exists in the event of temperatures becoming compromised.
Cold storage:- Cold storage refers to the storage of products requiring a storage temperature of
2ºC-8ºC, or when material is required to be stored frozen (e.g. below -20ºC or below -70ºC).
For a successful cold storage operation, the facility must select the right temperature recording
instrumentation, validate its processes and maintain documentation of records and procedures, including responding to alarm conditions.
Instruments used in warehouse:- the selection of recording instruments is vital. The
instruments must be easily read and the data must be retrievable. The instruments must be
calibrated to a national standard (the company should retain a copy of the calibration certificate
for the equipment) and a high/low temperature alarm should be incorporated. Max/min
thermometer is usually not acceptable.
Both air and product temperatures should be recorded. Note that air temperature can fluctuate
considerably more than product (often call “load”) temperature.
Validation and documentation of temperature control:- validation efforts must:
1. Prove that temperature mapping checks for areas of extreme temperatures.
2. Check on temperature variations during use.
3. Demonstrate performance in the event of a power failure.
4. Demonstrate the function of alarms.
5. Checking temperature records at the start of the waking day and recording these checks in a log.
When reviewing the cold storage controls, a program should be set up to review cold store
temperature records both weekly and monthly as part at a self inspection program.
Monitoring alarms:- Out-of-house alarm signals are often sent to remote contractors or security
offsite. It’s therefore very important to ensure the alarm system is operating reliably, as repeated
false signals may result in a real signal being ignored. There are many industry examples of
degraded stock due to late or no response to electrical failures in warehouses. The alarm system
should operate independently of the main electrical system.
There must be written procedure on how to respond and whom to inform when a temperature
alarm monitor signals a problem. This procedure should cover initial action (e.g. quarantine the
cold store) and subsequent action. There should be an available and current list of emergency
numbers to call, and there should be backup plans to relocate any products are of deterioration (e.g. frozen stock).
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